Fetal alcohol syndrome and related disorders are the leading known cause of mental retardation. Understanding the neuropathology of prenatal alcohol exposure is critical. Methods for preventing the brain damage are lacking due to limited understanding of alcohol disruption of neuronal development. To address this gap in knowledge, we are investigating the role of neuronal-glial interactions in alcohol-mediated neurotoxicity during development. Microglia are uniquely important because they mediate neuronal protection or, with pathologic activation, neuronal death. Our pilot studies reveal that exposure of neonatal rats to a single alcohol dose produces significant microglial loss in the developing cerebellum. In the surviving microglia, alcohol alters cell morphology and induces expression of activated antigens, suggesting pathological activation. Using microglial cultures, we found that alcohol induces microglial apoptosis and that alcohol-induced microglial cell death could be blocked by activation of the PPARgamma signaling pathway. [unreadable] To further these discoveries, this study will investigate the overall hypothesis that alcohol disruption of microglial-neuronal interactions, through induction of microglial apoptosis and pathologic microglial activation, contributes to alcohol neurotoxicity in the developing brain. Complementary in vivo and in vitro models will be used to test this hypothesis. Specific aims of this proposal are to: 1. Determine whether alcohol-induced microglial cell death is associated with neuronal apoptosis in the developing cerebellum. 2. Determine whether alcohol induces pathological activation of microglia and if alcohol-induced microglial activation is associated with neuronal apoptosis in the developing cerebellum. 3. Establish whether the deleterious effects of alcohol on developing microglia disrupt interactions between microglia and neurons and contribute to alcohol neurotoxicity. 4. Establish whether the deleterious effects of alcohol on microglia and neurons in the developing cerebellum involve suppression of PPARgamma signaling. Results of these studies will provide better understanding of alcohol interference with the relationship between microglia and neurons during development. Application of this knowledge may provide new therapeutic strategies for prevention or treatment of the neuropathology associated with prenatal alcohol exposure. [unreadable] [unreadable]